EXCEED THE SPACE PROVIDED. The central focus of our laboratory is to understand the molecular mechanisms that control development of the three muscle cell types; skeletal, cardiac, and smooth. Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors are the only known myogenic regulatory factors required for myogenesis and morphogenesis of all muscle cell types. These factors act combinatorially with other transcription factors to control muscle gene expression. In addition, recent studies have revealed important roles for MEF2 factors as transcriptional targets of calcium-dependent signaling pathways. Our results suggest that calcium-dependent signaling through MEF2 is important in cardiac hypertrophy and control of slow fiber gene expression in skeletal muscle. Gene knockout studies have demonstrated unique roles for each of the MEF2 genes, but also revealed a significant degree of functional redundancy among the genes. The goals of this project represent a logical extension of our previous studies and are designed to further define the functions of the vertebrate MEF2 genes, to identify key downstream target genes for MEF2 factors, and to identify the regulatory factors and signaling systems that act upstream of MEF2 genes in each myogenic lineage. Specifically, we intend to create conditional null alleles for MEF2 genes and genes encoding Class II histone deacetylases (HDACs) which act as signal- responsive repressors of MEF2. Using these conditional null alleles we will continue to refine our understanding of the regulatory interactions between MEF2 and HDAC during muscle development and remodeling. In addition, we will identify novel chemical regulators of MEF2-HDAC interaction and will focus particular attention on the function of a muscle specific kinase that is encoded by a direct target gene of MEF2. These studies will provide insights into fundamental mechanisms for development and disease and are likely to provide novel therapeutic targets for eventual treatment of cardiovascular disorders. PERFORMANCE SITE ========================================Section End===========================================
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